The polyamines, spermine/spermidine (SP/SD), are released in whole brain from unknown sources during neuronal[unreadable] activity. SP/SD dramatically alter the neuronal network and are neuroprotective against NMDA-induced neurotoxicity and[unreadable] ischemia. Intriguingly, endogenous SP and SD are predominantly stored in astrocytes, not in neurons. Our preliminary[unreadable] data suggest that SP/SD uptake and release by astrocytes may occur through unapposed gap junctions (hemichannels).[unreadable] This finding leads us to the novel working hypothesis that SP/SD are synthesized in neurons and permeate (i) connexin[unreadable] hemichannels in glia to ultimately be stored within the glial syncitium. (ii) Neuronal excitation results in a transient fall[unreadable] of [Ca2+]0 and [H+]0 together with increased [K+]0 that facilitates: (iii) opening of hemichannels in glia and (iv) release of[unreadable] SP from glia to the neuronal environment where it can act on AMPA, kainate and NMDA receptors, (v) Increased[unreadable] extracellular SP relieves residual hemichannel block by divalent cations, thus SP works as a positive feedback signal on[unreadable] glial hemichannels. We propose that SP/SD are signaling molecules that underlie a novel regulatory mechanism of[unreadable] neurons by glia. Furthermore, our preliminary experiments suggest that SP itself may facilitate hemichannel unblock,[unreadable] therefore, neuronal excitation may trigger a cascade, resulting in fast hemichannel opening. Here we ask: (i) what is the[unreadable] mechanism of SP permeation through hemichannels in glia, (ii) how is release of SP regulated under physiological[unreadable] conditions and (iii) what are the functional consequences of SP flux through the astrocytic membrane in a cortical slice[unreadable] preparation? These questions will be addressed by examining the mechanism of SP transport through hemichannels, by[unreadable] examining the effect of SP on heterologously expressed Cx hemichannels and by simultaneous recording from[unreadable] interneurons, astrocytes and principal cells while determining the relationship between opening of hemichannels, SP[unreadable] release and alterations in neuronal excitability. These studies will provide a novel mechanism for understanding the newly[unreadable] elucidated role of glial cells in the regulation of neuronal activity and to minimizing neuronal damage during K+-spreading[unreadable] depression, stroke and ischemia.